Vitamin D prescribing practices among clinical practitioners during the COVID‐19 pandemic

Abstract Background and Aims COVID‐19 has caused devastation globally. Low vitamin D status, particularly during the winter months, remains commonplace around the world, and it is thought to be one of the contributing factors toward causation and severity of COVID‐19. Many guidelines do not recommend vitamin D for the treatment or prevention of the disease. Hence, we set out to conduct a global survey to understand the use and prescribing habits of vitamin D among clinicians for COVID‐19. Methods An online anonymous questionnaire was sent to clinicians enquiring about their prescribing habits of vitamin D and personal use of vitamin D. Data of the survey were collected between January 15, 2021, and February 13, 2021. Results Four thousand four hundred forty practicing clinicians were included in the analysis, with the majority of those responding from Asia, followed by Europe. 82.9% prescribed vitamin D before COVID‐19, more commonly among general practitioners (GPs) in comparison with medical specialists, and Asian clinicians were more likely to prescribe vitamin D in comparison with Caucasian physicians (p < 0.01). GPs were also more likely to prescribe vitamin D prophylactically to prevent COVID‐19 in comparison with medical specialists (OR 1.47, p < 0.01). Most GPs (72.8%) would also prescribe vitamin D to treat COVID‐19 in comparison with medical specialists (OR 1.81, p < 0.01), as well as more Asian in comparison with Caucasian physicians (OR 4.57, p < 0.01). 80.4% of respondents were taking vitamin D, more so in the 45–54 and 65–74 age groups in comparison with the 18–24 years category (OR 2.15 and 2.40, respectively, both p < 0.05), many of whom did so before COVID‐19 (72.1%). Conclusion This survey has shown that many clinicians would prescribe vitamin D for the prevention and treatment of COVID‐19. The majority would also recommend measuring vitamin D levels, but not so in patients with COVID‐19.


| INTRODUCTION
The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated severe acute respiratory syndrome (SARS), 1 named by the World Health Organization (WHO) as coronavirus disease 2019  in January 2020, 2 has unequivocally become the greatest healthcare challenge faced by humankind in the 21st century. Following its incredibly rapid and severe spread, a global pandemic was declared by the WHO on March 11, 2020. 3 At that time, the number of affected individuals outside its originating country of China increased 13-fold, the pandemic spread in 114 countries, and 118,000 cases were registered, sadly causing nearly 4300 deaths. As of now, over 1 billion people worldwide have contracted COVID-19 and over 6 million deaths have occurred due to infection with SARS-CoV-2.
Several factors have been studied as possibly affecting the transmission and outcomes of COVID-19, including age, ethnicity, metabolic diseases, as well as environmental and social parameters such as temperature and air pollution. [4][5][6][7][8] Interestingly, some of these factors have also been linked to higher risk of vitamin D deficiency, 9 while a large number of studies regarding the possible association between vitamin D levels and the risk of COVID-19 contraction and worse outcomes have been published. [10][11][12][13][14][15] This link between vitamin D levels and COVID-19 outcomes can be explained based on the immunomodulatory actions of calcitriol, the interaction with the renin-angiotensin-aldosterone system (RAAS), as well as its protection against endothelial dysfunction and thrombosis. [16][17][18] Moreover, vitamin D suppresses cytokine production by simultaneously boosting the innate immune system, thus reducing the SARS-CoV-2 load, and decreasing the overactivation of the adaptive immune system to immediately respond to the viral load. 19 At the beginning of the pandemic when effective drugs and vaccines were not available, 20,21 there were physicians who prescribed treatments that were not proven to be useful: chloroquine, hydroxychloroquine (HCQ), azithromycin, 22,23 ivermectine, 24 and nitroxamide, 25 and advocate their use either for prevention or early treatment based on medical ethical autonomy to prescribe. The Solidarity Therapeutics Trial, 26 a very large randomized clinical trial (RCT) held in 30 countries over a period of 6 months, has shown little or no effect for remdesivir, HCQ, lopinavir/ritonavir, and interferon regimens on 28-day mortality or in-hospital course among patients hospitalized with COVID-19. Immunomodulatory agents (convalescent plasma, intravenous infusion of immunoglobulin, eculizumab) have also not shown any conclusive effects. 20 Previous data from a meta-analysis of 25 RCTs showed that vitamin D3 2000 IU daily supplementation has a protective action against acute respiratory infections and prophylactic use for COVID-19 has gained attention. 27 There has been much controversy toward its use and even more concerning the adequate dose. 28 Despite the lack of clinically robust data to support this therapy, many physicians eagerly prescribe generous doses of vitamin D, not in accordance with guidelines. A Brazilian study 29 using a high single oral dose of 5000 μg (200,000 IU) did not show any benefit on hospital stay duration in individuals with severe COVID-19 (n = 240); however, it should be mentioned that vitamin D supplementation began after the onset of moderate to severe COVID-19. Moreover, a smaller Indian trial involving 40 mild or asymptomatic patients with vitamin D deficiency, showed that a greater proportion of patients with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative after 21 days of vitamin D supplementation. 30 A recent study that evaluated the impact of vitamin D supplementation on the outcomes of COVID-19 found that supplementation was associated with reduced hospital stay and mortality and suggested the regulation of several factors such as the inducible nitric oxide synthase, interleukins, and cathelicidin-LL3. 31 In addition, a UK-based multicentre retrospective observational study (n = 986) showed that high-dose cholecalciferol booster therapy (approximately ≥280,000 IU in a time period of up to 7 weeks before hospital admission as part of routine clinical practice in cases of vitamin D insufficiency or deficiency) reduced risk of COVID-19 mortality regardless of baseline serum 25(OH)D levels. 32 A recent meta-analysis found that vitamin D supplementation reduces admissions to intensive care units, but not mortality, in patients with severe COVID- 19. 9 However, in the United Kingdom, the National Institute for Health and Care Excellence (NICE), Public Health England, and the Scientific Advisory Committee on Nutrition rapid guideline admit the lack of evidence, emphasizing the need for more research and reinforcing the previous UK government seasonal (October to March) policy for a daily 400 IU for both adults and children, and throughout the year for ethnic minority groups. 33 Despite the guidelines, there is a lot of support for the use of  Measured variables were the responses by the participating clinicians. Since this study was an anonymized survey and no personal information was obtained or stored from participants, it was deemed not necessary to require ethical approval and was given approval by the local research committee.

| Statistical methods
Data are expressed as n (%). Unadjusted logistic regression was used to determine whether participants were more or less likely to respond in a certain manner to each survey question, based on the following characteristics: specialty, ethnicity, age group, and whether the respondent cared for patients with COVID-19. The a priori levels of significance were two-sided and p < 0.05 were considered statistically significant. All analyses were carried out in Stata v 14.0 (StataCorp).

| RESULTS
A total of 5118 healthcare professionals responded; we excluded 678 responders because they were not practicing clinicians. The remaining 4440 practicing clinicians were included in the analysis. The demographics of the study participants are shown in Table 1.
Most participants were from Asia and mainly from India, followed by Europe. Most of the participants practiced medicine as specialists or general practice (GP)/family physicians and almost 64% were in the age group of 35-54 years. Most respondents (71.4%) participated in the care of patients with COVID-19, and most often they managed patients in an outpatient setting. p < 0.01). There were no significant relationships in prepandemic vitamin D prescribing patterns between age groups. These findings are summarized in Table 2.
With regard to the question "Would you prescribe vitamin D to prevent COVID-19?," 4393 answered. A total of 3385 (77.1%) clinicians responded that they would prescribe vitamin D to prevent COVID-19. General/family practitioners were significantly more likely to prescribe prophylactic vitamin D in comparison with medical

| DISCUSSION
The present study was performed to assess the knowledge and practices regarding vitamin D prescription among healthcare practitioners (HCPs) from different geographical regions and different specialties across the globe during the COVID-19 pandemic.
Vitamin D deficiency is highly prevalent globally, which has led to food fortification programs, especially in temperate countries with less sunshine. However, subtropical and tropical countries were not found to be free from vitamin D deficiency, despite plenty of sunshine. In addition, a low vitamin D level has been associated with depression. 38 Depression is common among the general population during the pandemic 39